Achieving site selectivity in C—H functionalization reactions is a significant challenge when the target C—H bonds are remote to existing functional groups. The development of a series of end-on templates has allowed for site-selective activation of remote meta-C—H bonds (more than 10 bonds away from the directing atom) [Leow et al., Nature 486, 518-522 (2012); Tang et al., Nature 507, 215-220 (2014); Lee et al., J. Am. Chem. Soc. 135, 18778-18781 (2013); Wan et al., J. Am. Chem. Soc. 135, 18056-18059 (2013); and Yang et al., J. Am. Chem. Soc. 136, 10807-10813 (2014)].
Coordination of a functional group to a metal catalyst is often a key driving force and control element in many important reactions including asymmetric hydrogenation [Brown, Chem. Soc. Rev. 22, 25-41 (1993)], epoxidation [Johnson et al., In Catalytic Asymmetric Synthesis, 2nd ed. (ed. Ojima, I.) 231-280 (John Wiley & Sons, Inc., Hoboken, 2005); and Li et al., Acc. Chem. Res. 46, 506-518 (2013)] and lithiation [Hartung et al., In Modern Arene Chemistry (ed. Astruc, D.) 330-367 (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2004)]. Exploitation of this effect has permitted the development of a diverse range of directed C—H activation reactions [Lyons et al., Chem. Rev. 110, 1147-1169 (2010); Daugulis et al., Acc. Chem. Res. 42, 1074-1086 (2009); Engle et al., Acc. Chem. Res. 45, 788-802 (2012); Colby et al., Chem. Rev. 110, 624-655 (2010); and Wencel-Delord et al., Chem. Soc. Rev. 40, 4740-4761(2011)].
However, these traditional C—H activation methods are limited to proximal C—H bonds that are spatially and geometrically accessible from the directing functional group. Development of meta-selective C—H functionalizations remains a significant challenge [Saidi et al., J. Am. Chem. Soc. 133, 19298-19301 (2011); Duong et al., Angew. Chem. Int. Ed. 50, 463-466 (2011); and Hofmann et al., J. Am. Chem. Soc. 135, 5877-5884 (2013)].
The inventor and co-workers recently developed a U-shaped template to overcome this constraint, which enables activation of remote meta-C—H bonds [Leow et al., Nature 486, 518-522 (2012); and Tang et al., Nature 507, 215-220 (2014)] illustrated schematically below. Although this
Covalent Template Strategy for Remote C—H Activation
approach has proven applicable for a diverse set of substrates and catalytic transformations [Lee et al., J. Am. Chem. Soc. 135, 18778-18781 (2013); Wan et al., J. Am. Chem. Soc. 135, 18056-18059 (2013); and Yang et al., J. Am. Chem. Soc. 136, 10807-10813 (2014)], the need for a covalently attached complex template is a significant drawback for synthetic applications. Inspired by the unique reactivity of norbornene in palladium-catalyzed reactions discovered by Catellani and co-workers, below, [Catellani et al., Angew. Chem. Int. Ortho-Alkylation and Ipso-Olefination in the Catellani Reaction
Ed. 36, 119-122 (1997); Faccini et al., J. Am. Chem. Soc. 126, 78-79 (2004); Martins et al., Top. Curr. Chem. 292, 1-33 (2010); Cardenas et al., J. Am. Chem. Soc. 128, 5033-5040 (2006); and Dong et al., J. Am. Chem. Soc. 135, 18350-18353 (2013)] it was hypothesized that ortho-palladacycle I could react with norbornene to provide an intermediate that can undergo activation of the meta-C—H bond (intermediate II), as shown below where ArF is perfluorinated p-tolyl [4-(CF3)C6F4].Norbornene as a Transient Mediator for Meta-C—H Activation

Reaction of palladacycle II with a coupling partner would form a new C—C or C-heteroatom bond and subsequent β-carbon elimination of norbornene followed by protodemetalation of the aryl-palladium bond would regenerate the palladium catalyst. As such, this reaction pathway would provide a new approach to achieve catalytic meta-selective C—H activation using standard ortho-directing groups with norbornene as a transient mediator.
The discussion that follows discloses the realization of this concept through the design of a pyridine-based ligand that suppresses several undesired reaction pathways and promotes meta-selective alkylation and -arylation of phenylacetic acid derivatives. This approach enables many previously reported ortho-C—H activation reactions to be achieved with high levels of meta-selectivity.